High Dose Folic Acid Supplementation Throughout Pregnancy for Preeclampsia Prevention

Preeclampsia Clinical Trial

— FACT  

Official title:

Effect of Folic Acid Supplementation in Pregnancy on Preeclampsia-Folic Acid Clinical Trial (FACT)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01355159
• Other study ID #: 2009-107
• Secondary ID: ISRCTN23781770
• Status: Completed
• Phase: Phase 3
• Start date: April 2011
• Est. completion date: September 2016

Study information

• Verified date: June 2020
• Source: Ottawa Hospital Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To determine the efficacy of high dose folic acid supplementation for prevention of preeclampsia in women with at least one risk factor: pre-existing hypertension, pre-pregnancy diabetes (type 1 or 2), twin pregnancy, preeclampsia in a previous pregnancy, or body mass index ≥35. It was hypothesized that high dose (4.0 mg per day) supplementation starting in early pregnancy and continued throughout the entire pregnancy will lower the incidence of preeclampsia in pregnant women at high risk of developing preeclampsia.

Description:

Preeclampsia is a complication of pregnancy which affects at least 5% of all pregnancies worldwide and has serious health consequences to these women and their babies. Preeclampsia is hypertension (high blood pressure) in pregnancy with proteinuria. Proteinuria is when protein is found in the urine, and it is a sign that the kidneys are not functioning properly. The only effective treatment for preeclampsia is delivery of the baby. Because delivery may be required before the anticipated date of delivery; preeclampsia is also one of the leading causes of preterm delivery and accounts for 25% of very low birth weight infants. Recent research has also shown that women who have had preeclampsia during pregnancy are more likely to be at risk for future cardiovascular events later in life.

Recently some studies have shown that supplementation with multivitamins containing folic acid is associated with a reduced risk of developing preeclampsia. These findings also suggested that for the prevention of preeclampsia, a high dose of folic acid (much higher than the amount of folate received from food intake or what is usually taken during pregnancy) may be needed.

A randomized controlled trial was conducted in 70 obstetrical centres in 5 countries (Argentina, Australia, Canada, Jamaica, and the UK) to evaluate the effect of high dose folic acid started in early pregnancy on the risk of developing preeclampsia in high-risk women. A sample size of 2464 allowed for 80% power and a 10% loss to follow-up/study withdrawal. Participants received either placebo or four 1.0 mg oral tablets of folic acid.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2464
• Est. completion date: September 2016
• Est. primary completion date: July 2016
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Capability of subject to comprehend and comply with study requirements

2. = 18 years of age at time of consent

3. Subject is taking =1.1 mg of folic acid daily at the time of randomization

4. Live fetus (documented positive fetal heart prior to randomization)

5. Gestational age between 8+0 and 16+6 weeks of pregnancy (Gestational age (GA) of subjects will be calculated based on the first day of the last menstrual period (LMP) or ultrasound performed before 12+6. If early ultrasound and LMP dates differ by = 7 days, base GA estimate on LMP date; if > 7 days, use early < 12+6 ultrasound)

6. Subject plans to give birth in a participating hospital site

7. Pregnant subjects must fulfill at least one of the following identified risk factors for pre-eclampsia (PE):

• Pre-existing hypertension (documented evidence of diastolic blood pressure = 90 mmHg on two separate occasions or at least 4 hours apart prior to randomization, or use of antihypertensive medication during this pregnancy specifically for the treatment of hypertension prior to randomization)

• Pre-pregnancy diabetes (documented evidence of Type I or type II DM)

• Twin pregnancy

• Documented evidence of history of PE in a previous pregnancy

• BMI > 35 kg/m2 within 3 months prior to this pregnancy and up to randomization of this pregnancy (documented evidence of height and weight to calculate BMI is required)

Exclusion Criteria:

1. Known history or presence of any clinically significant disease or condition which would be a contraindication to folic acid supplementation of up to 5 mg daily for the duration of pregnancy

2. Known major fetal anomaly or fetal demise

3. History of medical complications, including:

• renal disease with altered renal function,

• epilepsy,

• cancer, or

• use of folic acid antagonists such as valproic acid

4. Individual who is currently enrolled or has participated in another clinical trial or who received an investigational drug within 3 months of the date of randomization (unless approved by the Trial Coordinating Centre)

5. Known presence of:

• Alcohol abuse (= 2 drinks per day) or alcohol dependence

• Illicit drug/substance use and/or dependence

6. Known hypersensitivity to folic acid

7. Multiple Pregnancy (triplets or more)

8. Participation in this study in a previous pregnancy

Related Conditions & MeSH terms

• Pre-Eclampsia
• Preeclampsia
• Pregnancy Complications

Intervention

Drug:
• Folic Acid 4 mg
Folic Acid 1.0 mg or placebo x 4 tablets will be taken daily by oral administration. The majority of women in the study will routinely take 1.0 mg folic acid in a prenatal vitamin supplement, as recommended by their primary obstetrical provider; the study requirements do not require that participants change their practice. Therefore the actual total daily dose may be up to 5.1 mg of folic acid
• Placebo
Placebo x 4 tablets will be taken daily by oral administration.

Locations

Country	Name	City	State
Argentina	Cemic	Buenos Aires
Argentina	Hospital Escuela Eva Perón	Rosario	Santa Fe
Argentina	Hospital Provincial	Rosario	Santa Fe
Argentina	Hospital Roque Saenz Penia	Rosario	Santa Fe
Argentina	Maternidad Martin	Rosario	Santa Fe
Argentina	Sanatorio de la Mujer	Rosario	Santa Fe
Argentina	Hospital Cullen	Santa Fe
Argentina	Hosptial Iturraspe	Santa Fe
Australia	Townsville	Douglas	Queensland
Australia	Ipswich	Ipswich	Queensland
Australia	Adelaide	North Adelaide	South Australia
Australia	Royal Women's Hospital	Parkville	Victoria
Australia	Nepean	Penrith	New South Wales
Australia	Sunshine	St Albans	Victoria
Canada	Calgary Foothills Medical Center	Calgary	Alberta
Canada	Edmonton Lois Hole Hospital for Women	Edmonton	Alberta
Canada	Fredericton Dr. Everett Chalmers Regional Hospital	Fredericton	New Brunswick
Canada	Hamilton McMaster University	Hamilton	Ontario
Canada	Kingston	Kingston	Ontario
Canada	London	London	Ontario
Canada	Moncton Hospital	Moncton	New Brunswick
Canada	McGill University Royal Victoria Hospital	Montreal	Quebec
Canada	Quebec City (CHUL) Centre Hospitalier Universitaire	Montreal	Quebec
Canada	Saint-Luc CHUM - Montreal	Montreal	Quebec
Canada	Sainte-Justine	Montreal	Quebec
Canada	St-Mary's Hospital	Montreal	Quebec
Canada	Civic Hospital	Ottawa	Ontario
Canada	Ottawa Hospital	Ottawa	Ontario
Canada	Regina Qu'Appelle Health Region	Regina	Saskatchewan
Canada	Saint John Regional Hospital	Saint John	New Brunswick
Canada	Sault Ste- Marie Sault Area Hospital	Sault Ste. Marie	Ontario
Canada	St-John's Women's Health Centre	St John's	Newfoundland and Labrador
Canada	Sunnybrook Health Sciences	Toronto	Ontario
Canada	St-Paul's Hospital	Vancouver	British Columbia
Canada	Vancouver BC Women's Hospital and Health Center	Vancouver	British Columbia
Canada	Winnipeg St. Boniface General Hospital	Winnipeg	New Brunswick
Canada	Winnipeg University of Manitoba	Winnipeg	New Brunswick
Jamaica	Jubilee	Kingston
Jamaica	Spanishtown	Kingston
Jamaica	University of West Indies	Kingston 7
United Kingdom	Wansbeck General Hospital	Ashington	Northumberland
United Kingdom	Blackburn	Blackburn
United Kingdom	Burnley	Burnley
United Kingdom	Fairfield	Bury	Lancashire
United Kingdom	Cumberland Infirmary	Carlisle	Cumbria
United Kingdom	North Manchester	Crumpsall
United Kingdom	Darlington Memorial Hospital	Darlington	County Durham
United Kingdom	University Hospital of North Durham	Durham	County Durham
United Kingdom	Gateshead Queen Elizabeth Hospital	Gateshead	Tyne And Wear
United Kingdom	Northwick Park Hospital	Harrow	Middlesex
United Kingdom	Hinchingbrooke	Huntingdon	Cambridgeshire
United Kingdom	West Middlesex University Hospital	Isleworth	Middlesex
United Kingdom	Lincolnshire	Lincoln	Lincolnshire
United Kingdom	Guy's & St Thomas' Hospital	London
United Kingdom	St George's Hospital	London	Tooting
United Kingdom	South Tees Hospital	Middlesbrough
United Kingdom	Newcastle upon Tyne Hospitals	Newcastle upon Tyne
United Kingdom	North Tyneside General Hospital	North Shields
United Kingdom	Norfolk & Norwich	Norwich
United Kingdom	Nottingham City Hospital	Nottingham
United Kingdom	Nottingham Queens Medical Centre	Nottingham
United Kingdom	Oldham	Oldham
United Kingdom	Rochdale	Rochdale	Lancashire
United Kingdom	South Tyneside District Hospital	South Shields	Tyne And Wear
United Kingdom	Ormskirk	Southport	Merseyside
United Kingdom	North Tees Hospital	Stockton
United Kingdom	Sunderland Royal Hospital	Sunderland
United Kingdom	Hillingdon Hospital	Uxbridge
United Kingdom	Warrington and Halton Hospitals NHS Foundation Trust	Warrington	Cheshire
United Kingdom	West Cumberland Hospital	Whitehaven	Cumbria
United Kingdom	49 Marine Avenue & CCGs	Whitley Bay	Newcastle Upon Tyne
United Kingdom	The Royal Wolverhampton NHS Trust, New Cross Hospital	Wolverhampton	West Midlands

Sponsors (2)

Lead Sponsor	Collaborator
Ottawa Hospital Research Institute	Canadian Institutes of Health Research (CIHR)

Countries where clinical trial is conducted

Argentina,  Australia,  Canada,  Jamaica,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Preeclampsia	PE is defined as diastolic blood pressure =90 mmHg on two occasions =4 hours apart and proteinuria developed in women greater than 20+0 weeks of gestation. Proteinuria is defined as: urinary protein =300mg in 24 hour urine collection OR in the absence of 24 hour collection, =2+ dipstick proteinuria, OR random protein-creatinine ratio =30mg protein/mmol.; OR HELLP (Haemolysis, Elevated, Liver Enzymes, Low Platelets) syndrome defined as: Haemolysis (characteristic peripheral blood smear), Serum LDH = 600U/L, Serum AST = 70U/L, and Platelet count <100 x109/L; OR Superimposed pre-eclampsia, defined as history of pre-existing hypertension (diagnosed pre-pregnancy or before 20+0 weeks' gestation) with new proteinuria.	Participants will be followed from 20+0 weeks of gestational age until 42 days postpartum (after delivery)
Secondary	Maternal Death	According to the World Health Organization, "A maternal death is defined as the death of a woman while pregnant or within 42 days of termination of pregnancy, irrespective of the duration and site of the pregnancy, from any cause related to or aggravated by the pregnancy or its management but not from accidental or incidental causes.	Time Frame: Participants will be followed from 20+0 weeks of gestation until 42 days postpartum (after delivery)
Secondary	Spontaneous Abortion	Spontaneous abortion or miscarriage defined as death of a fetus <500g or <20 weeks of gestation	Participants will be followed from randomization until 20+0 weeks of gestation
Secondary	Placenta Abruption	Placental abruption (abruptio placentae) is the premature detachment of a normally positioned placenta from the wall of the uterus.	Participants will be followed from 20+0 weeks of gestation until delivery
Secondary	Premature Rupture of Membranes	Rupture of the membranes (rupture of the amniotic sac) before the onset of labor.	Participants will be followed from randomization (8-16 weeks' completed gestation) until the onset of labor
Secondary	Preterm Birth	Birth that occur earlier than 37+0 weeks of gestational age.	Participants will be followed from 20+0 weeks to 36+6 weeks of gestation
Secondary	HELLP (Hemolysis, Elevated Liver Enzyme Levels & Low Platelet Count)	Haemolysis (characteristic peripheral blood smear), Serum LDH >=600U/L, Serum AST >=70U/L, Platelet count <100 x109/L	Participants will be followed from 20+0 weeks of gestation until delivery
Secondary	Severe Preeclampsia	Severe PE: Defined as PE with convulsion or HELLP or delivery <34 weeks.	Participants will be followed from 20+0 weeks of gestation until delivery.
Secondary	Antenatal Inpatient Length of Stay	Length of inpatient stay before admission for delivery in days	Participants will be followed from date of randomization (8-16 weeks' completed gestation) until admission for delivery
Secondary	Stillbirth	Fetal death defined as death of fetus of at least 500 grams birth weight or, if birth weight is unavailable, a gestational age of at least 20+0 weeks of gestation.	Participants will be followed from 20+0 weeks of gestation up to delivery.
Secondary	Intrauterine Growth Restriction (<3rd Percentile)	Intrauterine growth restriction is defined as a birth weight less than the 3rd percentile of the population, adjusted for sex and gestational age, based on the current population-based Canadian reference standard.	Participants will be followed from 20+0 weeks of gestation until delivery
Secondary	Intrauterine Growth Restriction (<10th Percentile)	Intrauterine growth restriction is defined as a birth weight less than the 10th percentile of the population, adjusted for sex and gestational age, based on the current population-based Canadian reference standard.	Participants will be followed from 20+0 weeks of gestation until delivery
Secondary	Neonatal Death	Neonatal death defined as death of a baby that occurred during first 28 days of life.	Participants will be followed from birth until 28 days of life
Secondary	Perinatal Mortality	The perinatal mortality is defined as the number of deaths (fetal deaths and neonatal deaths) of babies = 500 grams birth weight or, if birth weight is unavailable, a gestational age = 20+0 weeks, up to 28 completed days after birth.	Participants will be followed from 20+0 weeks of gestation until 28 days of life.
Secondary	Retinopathy of Prematurity	Retinopathy of prematurity a retinopathy typically occurring in premature infants treated with high concentrations of oxygen, characterized by vascular dilatation, proliferation, tortuosity, edema, retinal detachment, and fibrous tissue behind the lens confirmed by retinal examination according to an International Committee for the Classification of Retinopathy of Prematurity.	Infants born to the participant will be followed for the duration of hospital stay, or up to 6 weeks
Secondary	Early Onset Sepsis	Within first 48hr of life, confirmed by positive blood or cerebrospinal fluid cultures	Infants born to the participants will be followed first 48 hours of life.
Secondary	Necrotising Enterocolitis	Necrotizing enterocolitis (NEC) according to modified Bell's criteria stage 2 or higher (grossly bloody stool, plus absent bowel sounds with or without abdominal tenderness and radiographic findings such as intestinal dilation, ileus, pneumatosis intestinalis), excluding isolated spontaneous intestinal perforations.	Infants borm to the participants will be followed for the duration of hospital stay, or up to 6 weeks.
Secondary	Intraventricular Hemorrhage (IVH)	IVH Grade 1(Blood in germinal matrix); IVH Grade 2 (Blood in germinal matrix and extending into the ventricles); IVH Grade 3 (Ventricular enlargement); IVH Grade 4 (Intraparenchymal lesion)	Time Frame: Infants born to the participants will be followed for the duration of hospital stay, or up to 6 weeks
Secondary	Ventilation	Ventilatory support after initial resuscitation, with/without intubation.	Infants born to the participants will be followed for the duration of hospital stay, or up to 6 weeks.
Secondary	Need for Oxygen at 28 Days		Infants to the participants will be followed for 28 days after birth.
Secondary	Composite Severe Adverse Fetal/Neonatal Outcome	Composite outcome included any of retinopathy of prematurity, periventricular leukomacia, early onset sepsis, necrotizing enterocolitis, intraventricular haemorrhage, ventilation. Need for O2at 28 days, NICU admission	Outcomes included in the composite outcome were measured for each of their respective time frames, up to 6-weeks after birth
Secondary	Length of Stay in 'High Level' Neonatal Care Unit		Infants to the participants will be followed for the duration of hospital stay, or up to 6 weeks.
Secondary	Neonatal Death	Neonatal death defined as death of the infant occurred before 28 days of life	Infants to the participants will be followed for 28 days after birth.
Secondary	Periventricular Leukomalacia	One of the two outcomes used to measure neonatal morbidity.	Infants to the participants were followed for 28 days after birth.
Secondary	Neonatal Intensive Care Unit (NICU) Admission	This outcome measured whether or not the infant was admitted into the NICU.	Infants to the participants will be followed for the duration of hospital stay, or up to 6 weeks.